Is ondansetron safe for use during pregnancy?

Gideon Koren, MD, FRCPC

October 2012

ABSTRACT

QUESTION

While I usually prescribe doxylamine-pyridoxine for morning sickness, some of my patients with severe nausea and vomiting of pregnancy (NVP) receive ondansetron in hospital. I have read some new precautions recommended by the US Food and Drug Administration (FDA). Is ondansetron safe to use during pregnancy?

ANSWER

During the past decade ondansetron has been increasingly used in the United States for NVP, owing to the lack of an FDA-approved drug for this condition. While fetal safety data for doxylamine-pyridoxine are based on more than a quarter of a million pregnancies, the fetal safety data for ondansetron are based on fewer than 200 births. Moreover, a recent case-control study suggested there was an increased risk of cleft palate associated with ondansetron. Recently, the FDA issued a warning about potentially serious QT prolongation and torsade de pointes associated with ondansetron use; the warning included a list of precautions and tests that must be followed. The drug is not labeled for use in NVP in either the United States or Canada. Based on the data available today, ondansetron use cannot be assumed to be safe during pregnancy.

Ondansetron, a potent antiemetic agent, is a 5-hydroxytryptamine receptor 3 antagonist that blocks the effects of serotonin. It was designed originally for chemotherapy-induced nausea and vomiting. The drug is also labeled for use in nausea and vomiting associated with radiation therapy, anesthesia, and surgery. However, because there is no drug approved by the US Food and Drug Administration (FDA) for morning sickness in the United States, an increasing number of American women experiencing nausea and vomiting of pregnancy (NVP) have been treated with ondansetron.

Fetal safety

Fetal safety of ondansetron was addressed by the Motherisk program in 2004 through a prospective cohort study of 176 women, mostly American, in whom we could not detect an increased teratogenic risk. 1 However, this sample size ruled out only a 5-fold increased risk of major malformations, and not any specific malformation. Moreover, the lack of other, similar cohort studies precluded conducting a meta-analysis to increase the sample size.

Importantly, a recent large control study by the Slone Epidemiology Center in Boston, Mass, and the Centers for Disease Control and Prevention in Atlanta, Ga, detected a 2-fold increased risk of cleft palate associated with ondansetron taken for NVP in the first trimester of pregnancy (odds ratio 2.37 [95% CI 1.28 to 4.76]). 2

Maternal safety

In September 2011 the FDA issued a warning about possible serious QT prolongation and torsade de pointes among people receiving ondansetron. 3 The FDA requires strict follow-up of patients receiving ondansetron to rule out long QT syndromes, electrolyte imbalance, congestive heart failure, or receiving concomitant medications that prolong the QT interval. 3 In the context of NVP, quite a few women with severe NVP might have electrolyte imbalances (hypokalemia or hypomagnesemia). Currently, through Motherisk counseling of women who receive ondansetron for morning sickness, it is evident that none of the FDA precautions are being followed.

Because the paramount challenge of treating pregnant women with medications is fetal and maternal safety, ondansetron should be used cautiously only after drugs with better safety records that have been labeled for use in pregnancy (eg, doxylamine-pyridoxine) have been tried.

Motherisk questions are prepared by the Motherisk Team at The Hospital for Sick Children in Toronto, ON. Dr Koren is Director of the Motherisk Program and is supported by the Research Leadership for Better Pharmacotherapy during Pregnancy and Lactation. He holds the Ivey Chair in Molecular Toxicology in the Department of Medicine at the University of Western Ontario in London.

Do you have questions about the effects of drugs, chemicals, radiation, or infections in women who are pregnant or breastfeeding? We invite you to submit them to the Motherisk Program by fax at 416 813-7562; they will be addressed in future Motherisk Updates.

Published Motherisk Updates are available on the Canadian Family Physician website (www.cfp.ca) and also on the Motherisk website.

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